Abstract

The immunotherapeutic ablation of lymphoma is a conceptually attractive treatment modality that is the subject of intense translational research activities. One approach being piloted through the City of Hope Lymphoma SPORE is the application of cellular immunotherapy employing cytolytic T-lymphocyte (CTL) grafts genetically engineered for CD19-specific effector functioning. This has been achieved by the construction of a chimeric T-cell antigen receptor (CAR) composed of a CD19-specific single chain immunoglobulin variable fragment (scFv) extracellular targeting domain molecularly coupled to the CD3 complex zeta chain. Cytolytic T-cells that are genetically modified to express this CAR display HLA-independent CD19-specific recognition and killing of lymphoma target cells. Using clinically applicable plasmid gene transfer/selection systems our group has demonstrated that anti-CD19 CAR+/HyTK+ CD8+ effectors can be generated from CTL precursors present in the peripheral blood and expanded to clinically relevant cell doses. We have designed an FDA-authorized (BB-IND#11411) clinical trial in which patients with recurrent/refractory follicular lymphoma undergo leukapheresis and a polyclonal CTL product derived that a.) expresses the anti-CD19 CAR, b.) kills CD19+ lymphoma targets, c) remains dependent on exogenous IL-2 for survival and proliferation, and d.) is sensitive to ganciclovir ablation by virtue of co-expression of the selection-suicide transgene HyTK. The trial is designed to assess the safety of intra-patient dose escalation beginning at a cell dose of 100x106 cells/m2 escalating to a dose of 2,000x106 cells/m2. In addition, this trial employs the use of rituximab to clear circulating B-cells prior to the first T-cell dose and fludarabine following the first T-cell infusion to both induce temporary lymphopenia and limit anti-transgene rejection responses. The protocol employs low-dose subcutaneous rhuIL-2 to support the numerical and temporal persistence of transferred CTLs. Treated patients are monitored with immunologic correlative studies that include Q-PCR for tracking persistence of transferred CTLs, RT-QPCR for following the levels of CD19+ B-cells in the peripheral blood, bone marrow, and lymph nodes, as well as, CT and PET imaging studies to follow disease responses. Here, we report on our initial clinical experience treating patients on this trial.

Author notes

Disclosure: No relevant conflicts of interest to declare.